Malaria remains one of the world's deadliest diseases, destroying lives by the millions and staggering families, communities and even nations with a burden that crushes hope. The demoralizing impact of the disease extends beyond the annual body count to effects on family and social structure, on sustained poverty in endemic areas, and in creating untold suffering for 40% of the world's population. The devastating situation is largely attributed to and aggravated by the emergence and spread of multi-drug resistant Plasmodium falciparum, the cause of the most deadly form of malaria. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against MDR malaria. With no available vaccine currently or in the near future, there is a dire need for novel, low cost, effective, safe, and sustainable malaria treatment. If a global effort to eradicate malaria is to be successful, both chemotherapeutic and chemoprophylactic components of that effort must address the gaps and weaknesses in the armamentarium of currently available therapies. Affordability, safety in the most vulnerable, and low susceptibility to drug resistance adaptations each represent unmet needs. In contrast to other drug classes (e.g., respiratory inhibitors and anti-folates), development of drug resistance to quinoline antimalarials has been slow (e.g., chloroquine) or of low order (e.g.,quinine). For older drugs in this class, cost is very low, there is extensive experience with their use in children and during pregnancy, and short-course therapy is facilitated by very long drug elimination times. Paradoxically then, although the failure of chloroquine is at the core of the global drug-resistance crisis, these drugs actually characterize the ideals now sought in new antimalarial drugs for both treatment and intermittent prophylaxis. The novel chemotype described in this proposal and in our recent publication featured in Nature represents a revolutionary approach. It specifically aims to exploit the strengths of other compounds with ideal traits by making possible a new combination therapy strategy. Our innovative acridone design addresses an immutable parasite target and merges intrinsic potency with resistance-counteracting functions in a single molecule, and is the first and only chemotype reported to do so. It represents a novel strategy to expand, enhance, and sustain effective antimalarial drug combinations. The ability to enhance the efficacy of newer drugs (e.g., piperaquine) and to restore the efficacy of older drugs (e.g., chloroquine) represents a uniquely powerful tool, and one ideally suited to achieve the broadest possible benefit as a renewed malaria eradication effort proceeds. Given the scope of the global impact of malaria, the significance of success in these efforts would be nothing less than improving the lives of millions of individuals and the chance to change the face of entire nations. PUBLIC HEALTH RELEVANCE: This application entitled "Dual Function Acridones As A New Antimalarial Chemotype" addresses broad Challenge Area (15) Translational Science and specific Challenge Topic 15-AI-103: Develop drugs for neglected tropical diseases, with a special emphasis on malaria. We have discovered and seek to improve dual function antimalarial acridones for treatment of malaria. Millions die each year from malaria, and there is a great need for new antimalarial drugs that are effective against multi-drug resistant infection, safe in children and during pregnancy. If these drugs prove to be safe and effective enough to go into actual use, the potential benefit is nothing less than saving millions of lives.